2. Background Commissioned call NIHR HTA Objective: To determine if invasive ventilation using protocolised weaning that includes non- invasive ventilation (NIV) as an intermediate step is clinically and cost effective compared to protocolised weaning without NIV

3. Study summary Design: Pragmatic, open label, RCT Population: Adults, ventilated > 48 hr, fail SBT Intervention: Weaning using NIV Comparator: Protocolised invasive weaning Outcome: Time to liberation from ventilation Sample size: 920 over 30 months

4. Study Timeline

5. Recruitment Plan Target for sites 1.5 patients per month

6. Outcomes Primary clinical outcome: Time from randomisation to liberation from ventilation

7. Secondary clinical outcomes 30, 90 and 180 day all cause mortality Duration of invasive mechanical ventilation and total ventilator days Time to meeting ICU discharge criteria Hospital length of stay Antibiotic use Re-intubation, tracheostomy; adverse events Health related quality of life

8. Inclusion criteria Is the patient age 16 years or older? Has the patient received invasive mechanical ventilation for respiratory failure for greater than 48 hours? Is the patient ready for weaning?

9. Exclusion criteria Patient known to be pregnant Presence of tracheostomy Profound neurological deficit Any absolute contraindication to NIV Home ventilation prior to ICU admission Decision not to re-intubate / withdrawal Further surgery / procedure requiring sedation planned in next 48 hours Previous participation in the Breathe study

10. Daily Screening All ventilated patients will be assessed each morning for eligibility by ICU nursing / medical staff. Patients will be identified as potentially eligible if they fulfil the following criteria: anticipated or actual requirement for invasive ventilation for > 24 hours at least partial reversal of the condition precipitating invasive ventilation stabilisation of "other" organ system failures (i.e. no worsening) arterial oxygen saturation measured using pulse oximetry (SpO2) ≥ 90% with fractional concentration inspired oxygen (FiO2) ≤ 0.70 PEEP ≤ 10 cmH2O the absence of trial exclusion criteria (above) A screening log will be maintained at each site which will include the reasons for non-enrolment.

11. Obtain consent Spontaneous Breathing Trial Record baseline characteristics Excluded PASS Daily screening for eligibility and assess for readiness to wean RANDOMISE Protocolised NIV weaning arm Protocolised Invasive weaning arm FAIL

13. * England, Wales, NI CONSENT PROCESS

14. Cooperative and pain free Good cough PaO 2 : FiO 2 ratio >24 kPa PEEP <10 cmH 2 O Hb >7 g dL -1 Temperature 36 - 38.5°C Vasoactive drugs stable Spont respiratory rate >6 min -1 Readiness to wean Walsh BJA 2004

15. Record baseline characteristics Exhaled minute volume Total respiratory rate PEEP Plateau pressure Heart rate Systolic blood pressure Arterial blood gases

16. SBT To be performed in accordance with local unit practices 30 mins duration T-piece Psupp 5cm H 2 O CPAP Pass – Extubate Fail - Randomise Ely N Engl J Med 1996

18. Standardised protocols Ventilator care bundle – head up position; oral decontamination; sedation hold; peptic ulcer prophylaxis Tracheostomy – More than 7 days IMV; inability to protect airway; persistent inability to remove respiratory secretions Re-intubation – Protocolised and clinical endpoints

19. Data collection

20. Baseline variables Patient identifiers Inclusion and exclusion criteria APACHE II (at admission) Admission diagnosis Presence of COPD Height and weight Duration of ventilation prior to randomisation CAM-ICU

21. Daily data Ventilation status (IMV, NIV, self- ventilating) Organ support requirements Level of critical care Antibiotic use for respiratory and non- respiratory infection Adverse events Sedation usage Weaning and ventilator bundle compliance

22. Study endpoints Liberation from ventilation – Add definition from CRF Death Tracheostomy Re-intubation – Actual – Protocolised ICU discharge data Discontinuation of intervention NIV arm – re-intubation IPPV arm – tracheostomy Withdrawal of consent Need to continue data collection after discontinuation of intervention until ICU / hospital discharge Endpoints

23. After discharge Before hospital discharge (on site) Consent Antibiotic use if started within ICU Acute hospital discharge date and status HRQoL After hospital discharge (WCTU) Survival to 180 days EQ-5D and SF-12 Healthcare resource use questionnaire

24. Serious Adverse Events A serious adverse event is an AE that fulfils one or more of the following criteria: Results in death Is immediately life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Is a congenital abnormality or birth defect Is an important medical condition. The causality of SAEs (i.e. relationship to trial treatment) will be assessed by the investigator(s) and recorded on the SAE form. **Do not report death, pneumonia, organ failure as SAE**

25. Safety Reporting All suspected SAE’s report to Warwick Clinical Trials Unit within 24 hours (Tel: 02476 575849 Fax: 02476 150549)

26. Patient Follow-up Health-related quality of life: EQ-5D, SF12 at baseline (estimated) Patient follow-up: 3 and 6 months EQ-5D and SF12

27. Study team Chief Investigator:Prof Gavin Perkins Project Manager:Sarah Duggan Trial Coordinator:Bev Hoddell Trainee Trial Coordinator:Jess Smith Research Facilitator:Laura Blair Research Nurse:Vikki Gordon

28. Pilot Study Sites Hospital PIResearch Nurse HEFT – HeartlandsProf Fang Gao-SmithPeter Sutton UHCWChris BassfordMarie McCauley Guys & St Thomas’Nick Hart & Luigi CamporotaKatie Lei/John Smith QEHBCatherine SnelsonArlo Whitehouse Bristol RITim Gould & Sanjoy ShahKatie Sweet RVH BelfastDanny McAuley JR OxfordDuncan Young

29. Questions? Contact: Bev Hoddell, Trial Coordinator. Tel No: 02476-575849 Email: b.hoddell@warwick.ac.uk Address: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7ALb.hoddell@warwick.ac.uk